This competing continuation application proposes a set of patient studies of the serotonergic system in major depression and the effects of somatic antidepressants on the serotonergic system, that builds on findings from the current funding period where we observed higher 5- HT1A autoreceptor binding in both bipolar and MDD major depressive episodes, an effect that persists in long-term remitted MDD off medication and that is unaffected by a six week treatment period on SSRIs. This picture is consistent with a biochemical trait which may be due to genetic or enduring consequences of childhood adversity and explain the predisposition to recurrent episodes of mood disorders. We find that this elevation in autoreceptor binding is associated with greater frequency of the higher expressing G allele in a promotor polymorphism G (-1910) C in this gene. This allele is associated with higher expression in raphe and not hippocampal neuron cultures and we therefore hypothesize that higher autoreceptor binding that we have also shown to have G allele dose-dependent association, is part of the primary psychopathology of at least one type of hyposerotonergic depression where the firing rate of serotonin neurons is low due to more autoreceptors. Changes in post-synaptic terminal field 5- HT1A binding are thought to be secondary and may represent up-regulation or supersensitivity in response to less serotonin release. In the current funding period, we have developed a method for quantifying 5-HT1A agonist binding in vivo using positron emission tomography (PET) and a new ligand [11C]CUMI-101. We have acquired pilot data showing the tracer is an agonist, displaceable by full agonists, accounts for about half the binding level of an antagonist indicating that the ratio of high to low affinity binding sites is about 2:1, but varies across brain regions and cannot be predicted by the level of antagonist binding. We have completed toxicology, safety and dosimetry studies qualifying the tracer for human use. We now propose to systematically determine high and low affinity 5-HT1A binding in a major depressive episode in both MDD and bipolar disorders by sequential PET scans of [11C] CUMI-101and [11C] WAY-100635, where the injections are separated by 6 half-lives. The functional effects of more binding are to be found in the level of high affinity binding including supersensitivity due to low serotonin in terminal fields of depressed and the hypothesized desensitization of auto-receptors by SSRIs, to date only detected in animal studies.